Epidemics account for a small proportion of preventable infections acquired in hospitals, but they have been important in defining sources, modes of spread, and methods for prevention and control of nosocomial infections. To characterize hospital-based epidemics, 265 consecutive outbreaks investigated by the Center for Disease Control between 1956 and 1979 were reviewed. Pseudoepidemics were found in 11 percent of the investigations, most often resulting from errors in processing microbiologic specimens or from surveillance artifacts. In 223 actual epidemics, the pathogens most commonly involved were Staphylococcus aureus (19 percent), tribe Klebsielleae (14 percent), Salmonella (13 percent), hepatitis B virus (8 percent), enteropathogenic Escherichia coli (5 percent), Pseudomonas (4 percent) and group A streptococci (4 percent). Sites of epidemic infection were closely linked to the responsible pathogens. Gastroenteritis (21 percent), skin infection (18 percent), bacteremia (12 percent), meningitis (11 percent) and hepatitis (10 percent), infrequent causes of endemic nosocomial infections, were frequently involved in epidemics. Over the 25-year period reviewed, staphylococcal epidemics and outbreaks of gastroenteritis due to Salmonella and Esch. coli declined in frequency and those due to gram-negative bacilli and hepatitis B virus increased. Since 1970, clusters of primary bacteremia were the most frequently investigated type of epidemic. Many epidemic strains of staphylococci obtained since 1975 or Enterobacteriaceae obtained since 1970 exhibited unusual drug resistance. Specific site-pathogen combinations were closely associated with characteristic reservoirs and modes of spread.